Mortality of oysters Crassostrea gigas occurred along the coasts of France during summer 2008, causing a serious crisis in French oyster production. During spring to summer 2008, 5 groups of 1-yr old oysters of different origins and ploidy levels deployed in the Thau lagoon (France) were sampled for biometrical and biochemical analyses; environmental parameters were monitored in the same area. Mortality occurred in 2 episodes: 13 May to 10 June and 24 June to 9 July. Wild-collected oysters showed mortality sooner than other groups but total overall mortality was 85% in all groups. Mortality occurred when seawater temperature was >19°C during the reproductive season when energetic reserves of oysters were at their lowest. Energy reserve levels and mortality in oysters seemed to be independent of reproductive effort, and most likely reflected an unusual deficit in phytoplankton. The level of bacterial fatty acids in oysters increased markedly before the second mortality event, probably indicating an enhancement of the microbial loop or decomposition processes. At the same time, unsaturation of oyster fatty acids decreased, suggesting a diet change, acclimatization to increasing temperature or, most likely, oxidative damage due to an enhanced production of reactive oxygen species, which are often associated with stressful situations. Wild-collected and hatchery-produced oysters, which exhibited different mortality patterns, showed persistent differences in fatty acid (20:5n-3 and 22:6n-3) content in their membrane, despite the fact that they were reared in the same environment. Mortality started when fatty acid 20:4n-6 content increased to ~3% in the polar lipids, suggesting that this ratio could make a useful indicator of mortality risk. Finally, the 2008 mortality event coincided with a nationwide increase of ~1.5°C in winter seawater temperature, which may impact the oyster and its pathogens.